The long term goal of this project is to investigate the functions of nicotinic receptor subpopulations in brain, focusing on potential cytoprotective and memory-enhancing actions of alpha7 receptors for the treatment of Alzheimer's disease. Several hypotheses will be tested: 1) alpha7 receptors protect against apoptotic and necrotic neurotoxic insults by sequentially increasing intracellular calcium concentrations, increasing protein kinase C (pkc) translocation, and elevating bcl-2 levels; 2) accumulation of intracellular calcium ions by the alpha7 selective agonist DMXB is mediated through voltage sensitive calcium channels; 3) mixed agonist/antagonist activity at alpha7 receptors interferes with neuroprotection by attenuating receptor-mediated calcium accumulation; 4) DMXB protects axotomized septal cholinergic neurons selectively by a mechanism that involves activation of septal alpha7 receptors; and 5) alpha7 receptor activation is sufficient to improve memory-related behavior in aged animals. These studies use a combination of approaches, including: enzyme-assays, immunoblotting, histochemistry, patch clamp electrophysiology, and morphological analyses. A variety of assays (e.g., calcium-accumulation, PKC activity, bcl-2 immunohistochemistry) will be conducted in the Chemistry Core associated with this grant.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG010485-11
Application #
6481568
Study Section
Project Start
2001-08-01
Project End
2002-07-31
Budget Start
Budget End
Support Year
11
Fiscal Year
2001
Total Cost
Indirect Cost
Name
University of Florida
Department
Type
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Richter, Frank; Koulen, Peter; Kaja, Simon (2016) N-Palmitoylethanolamine Prevents the Run-down of Amplitudes in Cortical Spreading Depression Possibly Implicating Proinflammatory Cytokine Release. Sci Rep 6:23481
Means, John C; Gerdes, Bryan C; Kaja, Simon et al. (2016) Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging. Neurochem Res 41:2278-88
Montgomery, Christa L; Keereetaweep, Jantana; Johnson, Heather M et al. (2016) Changes in Retinal N-Acylethanolamines and their Oxylipin Derivatives During the Development of Visual Impairment in a Mouse Model for Glaucoma. Lipids 51:857-66
Kaja, Simon; Payne, Andrew J; Singh, Tulsi et al. (2015) An optimized lactate dehydrogenase release assay for screening of drug candidates in neuroscience. J Pharmacol Toxicol Methods 73:1-6
Sarkar, Saumyendra; Jun, Sujung; Simpkins, James W (2015) Estrogen amelioration of A?-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ER?, AKAP and Drp1. Brain Res 1616:101-11
Kaja, Simon; Payne, Andrew J; Naumchuk, Yuliya et al. (2015) Plate reader-based cell viability assays for glioprotection using primary rat optic nerve head astrocytes. Exp Eye Res 138:159-66
Cheli, V T; Santiago González, D A; Spreuer, V et al. (2015) Voltage-gated Ca2+ entry promotes oligodendrocyte progenitor cell maturation and myelination in vitro. Exp Neurol 265:69-83
Kaja, Simon; Sumien, Nathalie; Shah, Vidhi V et al. (2015) Loss of Spatial Memory, Learning, and Motor Function During Normal Aging Is Accompanied by Changes in Brain Presenilin 1 and 2 Expression Levels. Mol Neurobiol 52:545-54
Kaja, S; Payne, A J; Nielsen, E Ø et al. (2015) Differential cerebellar GABAA receptor expression in mice with mutations in CaV2.1 (P/Q-type) calcium channels. Neuroscience 304:198-208
Grillo, Stephanie L; Koulen, Peter (2015) Psychophysical testing in rodent models of glaucomatous optic neuropathy. Exp Eye Res 141:154-63

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